1. Field of the Invention
The present invention relates to novel compounds that are potent inhibitors of αLβ2 integrin mediated cell adhesion which could be useful for the treatment of αLβ2 integrin mediated inflammatory conditions.
2. Description of Related Art
Leukocyte integrins and intercellular adhesion molecules (ICAMs) play pivotal roles in leukocyte adhesion to target cells and extracellular matrices. The β2 (CD18) integrin subfamily has four members, each consisting of a related but distinct α-chain noncovalently paired with CD18: αLβ2 integrin (LFA-1, CD11a/CD18), αMβ2 integrin (Mac-1, CD11b/CD18), αXβ2 integrin (p150/95, CD11c/CD18), and αDβ2 integrin (CD11d/CD18) (Bochner ed., Adhesion Molecules in Allergic Disease, Marcel Dekker, Inc. pp 1-24 (1997)). Among them, LFA-1 has been shown to be central to the cell adhesion and transendothelial migration of T cells, eosinophils, and other leukocytes into inflamed tissues (Garmberg, Curr. Opin. Cell Biology, 9, 643-650 (1997); Panes et al., Br. J. Pharmacology, 126, 537-550 (1999)). LFA-1 binds to the ICAM family (ICAM-1, -2, -3, -4, -5) of molecules expressed on multiple cell types such as vascular endothelial cells, dendritic cells, epithelial cells, macrophage and T lymphoblasts (Dustin et al., J. Immunology, 137, 245-254 (1986)). In addition, LFA-1/ICAM-1 and LFA-1/ICAM-3 interactions can act as co-stimulatory signals required for T cell activation (Wingren et al., Crit. Rev. in Immunology, 15, 235-253 (1995)).
Cell migration and T cell co-activation are important processes in a number of inflammatory disease states. A dominant role of LFA-1 in mediating inflammatory events is shown in several different animal models of inflammatory diseases in which antibodies to LFA-1 or ICAM-1 significantly inhibit development of therapeutic end points (Rothlein et al., Kidney International, 41, 617 (1992); Iigo et al., J. Immunology, 147, 4167 (1991); Bennet et al., J. Pharmacol. and Exp. Therapeutics, 280, 988 (1997)). In addition, a humanized monoclonal antibody to CD11a (the alpha chain of LFA-1) has shown efficacy in patients with psoriasis (Gottlieb et al., J. Am. Acad. Dermatology, 42, 428-35 (2000)).
Moreover, it has been shown that antibodies against LFA-1 suppress rejection after organ transplantation (Poston et al., Transplantation 69, 2005-2013 (2000); Nakakura et al. Transplantation 62, 547-552 (1996)). WO 94/04188 discloses the use of monoclonal antibodies directed against αLβ2 integrin for all transplantations.